Relapse to drug use following periods of abstinence is a significant impediment in the long-term treatment of cocaine dependence. Environmental stimuli or contexts previously associated with drug use or priming doses of the abused drug can initiate relapse to compulsive drug-seeking and drug-taking behaviors. Project 4 will take intervention strategies identified through the NARC projects aimed at reducing relapse to cocaine-seeking and systematically test compounds that will hopefully show significant and selective attenuation of cocaine-seeking in the relapse model. The advantages of having such a project within the NARC include: a) the ability to use standardized procedures through the NARC Animal Core of cocaine selfadministration and reinstatement, b) testing acute and chronic drug treatment protocols that inhibit cocaineseeking that can be further used in other NARC projects to assess the validity of cocaine-induced neuroplasticity for drug target development, and c) integrating the NARC preclinical animal model of relapse with potential clinical projects in the NARC Pilot Core as a transition to clinical assessment of promising pharmacotherapies. Project 4 will initially focus on a few selected strategies of drug intervention by targeting dopaminergic activity via a partial DA receptor agonist, enhancement of glutamatergic homeostasis, and antagonism of the orexin receptor. The proposed experiments will assess the effects of drug intervention after varied periods of cocaine-taking history, during and after extinction training, following abstinence in the absence of extinction, and in response to both conditioned cues and cocaine priming injections. Additional experiments will determine the effects of test compounds on ongoing cocaine-taking and responding for non-drug reinforcement (i.e., food). Since the focus of Project 4 will be the assessment of compounds that can be quickly applied in a clinical environment, we will initially focus on systemically available, approved drugs for use in humans. However, in years 4-5 of the proposed NARC renewal, we intend to take identified compounds from other NARC Projects that can be thoroughly assessed using the relapse model. In summary, Project 4 will provide for the systematic examination of testable drug interventions derived from studies within the NARC. Other projects within the NARC, in particular Project 1, will identify future targets of intervention as anti-relapse medications. By applying a seamless model of testing in conjunction with the NARC Animal Core, we will establish a template for the testing of putative medications as they are derived from NARC projects to serve as a bridge to clinical testing of such agents through the NARC Pilot Core. The results from these integrated studies will hopefully lead to useful pharmacotherapeutic agents for the